Heparin is a naturally occurring glycosaminoglycans (GAGs) that is synthesized by and stored intracellulary in so-called mast cells in humans and animals. Prepared industrially from porcine intestinal mucosa, heparin is a potent anticoagulant and has been used clinically for more than 60 years as the drug of preference for prophylaxis and treatment of thromboembolic disorders. The major potential adverse effects of heparin treatment are bleeding complications caused by its anticoagulant properties. Heparin is highly polydisperse and composed of a heterogeneous population of polysaccharides with molecular weights ranging from 5 to 40 kDa, with the average being approximately 15 to 18 kDa
Low molecular weight/mass heparins (LMWH) according to European pharmacopeia 6.0 are defined as “salts of sulfated GAGs having a mass-average molecular mass less than 8 and for which at least 60 percent of the total mass has a molecular mass less than 8 kDa.” “Low molecular mass heparins display different chemical structures at the reducing or the non-reducing end of the polysaccharide chains.” “The potency is not less than 70 IU of anti-factor Xa activity per milligram calculated with reference to the dried substance. The ratio of anti-factor Xa activity to anti-factor IIa activity is not less than 1.5.” Clinically used LMWHs have molecular weights ranging from 3 to 15 kDa with an average of approximately 4 to 7 kDa. Produced by controlled depolymerization/fractionation of heparin, LMWHs exhibits more favorable pharmacological and pharmacokinetic properties, including a lower tendency to induce hemorrhage, increased bioavailability and a prolonged half-life following subcutaneous injection. Heparin exerts its anticoagulant activity primarily through high-affinity binding to and activation of the serine proteinase inhibitor, antithrombin (AT). Binding is mediated by a specific pentasaccharide sequence. AT, an important physiological inhibitor of blood coagulation, neutralizes activated coagulation factors by forming a stable complex with these factors. Binding of heparin causes a conformational change in AT that dramatically enhances the rate of inhibition of coagulation factors, thereby attenuating blood coagulation and the formation of blood clots.
Sickle cell disease (SCD) is an inherited disorder due to homozygosity for the abnormal hemoglobin, hemoglobin S (HbS). This abnormal HbS is caused by the substitution of a single base in the gene encoding the human (3-globin subunit. Its reach is worldwide, but predominantly affects people suffering from malaria, primarily in equatorial Africa, but also in the Mediterranean-, India, and Middle East. The vaso-occlusive phenomena and hemolysis are clinical hallmarks of SCD. Vaso-occlusion results in recurrent painful episodes (sometimes called sickle-cell crisis) and a variety of serious organ system complications such as secondary infections, acute chest syndrome, stroke, and splenic sequestration. Vaso-occlusion accounts for 90% of hospitalizations in children with SCD, and it can ultimately lead to life-long disabilities and/or early death. On a molecular level, P-selectin is one of several targets that have been shown to be an important receptor in mediating the adhesion of blood cells to the vessel wall as part of the events leading to vaso-occlusion.
The presently dominating therapy of managing SCD includes the use of hydroxyurea (Ware et al American Society of Hematology, 2009, pp 62-65). However, this treatment has only limited efficacy and includes a number of side-effects for the patients. Chaplin et al (see East Afr Med J. 1989; 66(9):574-84) performed a pilot trial with daily prophylactic dose of heparin in four patients with sickle cell crises and successfully demonstrated pain reduction and fewer days at hospital. Qari et al. (Thromb. Haemost, 2007, 98, 392-6) describe a clinical study where a low molecular weight heparin derivative, tinzaparin, was used, reporting beneficial effects of the treatment, but also several cases of bleeding events.
WO 03/088980 suggests an oral treatment with heparin or heparin subfractions for the treatment of vaso-occlusion (VOC) in SCD.